Modified Project Summary/Abstract Section Nutrition during early life is critically important in establishing the lifelong trajectory of metabolic disease risk, however the precise mechanisms by which neonatal nutrient exposures shape long-term structure and function of metabolic tissues are not well understood. Stressors during critical developmental windows have been shown to increase offspring risk of obesity, diabetes and non-alcoholic fatty liver disease. The early postnatal critical window is of key importance for metabolic programming and one when infant growth trajectory is modifiable. The long-term goal of this work is to understand if a neonatal intervention can reduce lifetime metabolic disease risk. To address knowledge deficits in how early postnatal nutrient exposures impact energy metabolism in adulthood we have developed an animal model of high fat diet exposure during the postpartum period. Our preliminary data has shown that male offspring from this model demonstrate increased adiposity, insulin resistance, hepatic steatosis and glucose intolerance. We will use this model to study how excess maternal nutrient intake during this short exposure window programs both male and female offspring metabolic trajectory. The objectives of this application are to determine the changes in breast milk composition that result from prevalent patterns of dietary fat intake and determine the ability of targeted early postnatal interventions to rescue programming by maternal high fat diets during lactation. We will pursue the following specific aims: 1. Determine the role that specific breast milk fatty acids play in programming liver insulin resistance and 2. Determine if interventions to alter milk fatty acids can reverse offspring programming of liver insulin resistance. Completion of these aims will allow for the design of targeted interventions and will pinpoint the timing of interventions to reverse or arrest the progression of insulin resistance and its metabolic consequences. This work will make a significant contribution to the field of developmental programming of metabolic disease by advancing our understanding of the lasting impact of early life nutrient exposures that alter breast milk composition on offspring metabolic tissue structure, lipid handling and regulation of key nutrient sensing pathways.